1. Field of the Invention
The present invention relates to N-oxides of Mannich bases of drugs and prodrugs containing acidic N—H groups and having activity for treating hyperproliferative disorders and the use thereof as drugs or prodrugs. Further, the invention relates to methods of using the compounds, alone or in combination with one or more other active agents or treatments, to treat hyperproliferative disorders.
2. Related Art
One in every four deaths in the United States is due to cancer, and cancer is the second leading cause of death. U.S. Cancer Statistics Working Group; United States Cancer Statistics: 1999-2001 Incidence, Atlanta (Ga.): Department of Health and Human Services, Centers for Disease Control and Prevention, and National Cancer Institute (2004). The National Cancer Institute reports that almost 10 million Americans have a history of invasive cancer, while the American Cancer Society estimates that in the year 2004, over 1.3 million Americans will receive a diagnosis of invasive cancer with over a half million cases resulting in death. American Cancer Society, Cancer Facts & Figures 2004. These statistics exclude the 1 million cases of basal and squamous cell skin cancers that are expected to be diagnosed in the United States.
Cancers are classified based on the organ and cell tissue from which the cancer originates, including: (i) carcinomas (most common kind of cancer which originates in epithelial tissues, the layers of cells covering the body's surface or lining internal organs and various glands); (ii) leukemias (origination in the blood-forming tissues, including bone marrow, lymph nodes and the spleen); (iii) lymphomas (originates in the cells of the lymph system); (iv) melanomas (originates in the pigment cells located among the epithelial cells of the skin); and (v) sarcomas (originates in the connective tissues of the body, such as bones, muscles and blood vessels). (See Molecular Biology of the Cell: Third Edition, “Cancer,” Chapter 24, pp. 1255-1294, B. Alberts et al., (eds.), Garland Publishing, Inc., New York (1994); and Stedman's Pocket Medical Dictionary; Williams and Wilkins, Baltimore (1987)). Within these broad cancer classifications, there are over one hundred cancer subclassifications, such as breast, lung, pancreatic, colon, and prostate cancer, to name a few.
Cancer cells develop as a result of damage to a cell's DNA (i.e., altered DNA sequence or altered expression pattern) from exposure to various chemical agents, radiation, viruses, or when some not-yet-fully-understood internal, cellular signaling event occurs. Most of the time when a cell's DNA becomes damaged, the cell either dies or is able to repair the DNA. However, for cancer cells, the damaged DNA is not repaired and the cell continues to divide, exhibiting modified cell physiology and function.
Neoplasms, or tumors, are masses of cells that result from an aberrant, accelerated rate of growth (i.e., hyperproliferative cell growth). As long as the tumor cells remain confined to a single mass, the tumor is considered to be benign. However, a cancerous tumor has the ability to invade other tissues and is termed malignant. In general, cancer cells are defined by two heritable properties: the cells and their progeny 1) reproduce in defiance of normal restraints, and 2) invade and colonize the territories of other cells.
Cancerous tumors are comprised of a highly complex vasculature and differentiated tissue. A large majority of cancerous tumors have hypoxic components, which are relatively resistant to standard anti-cancer treatment, including radiotherapy and chemotherapy. Brown, Cancer Res. 59:5863 (1999); and Kunz, M. et al., Mol. Cancer 2:1 (2003). Thomlinson and Gray presented the first anatomical model of a human tumor that describes a 100 to 150 μm thick hypoxic layer of tissue located between the blood vessels and necrotic tumor tissues.
Research has shown that the hypoxic tissues within a number of cancerous tumors promote the progression of the cancer by an array of complex mechanisms. See, Brown., supra, and Kunz et al., supra. Among these are activation of certain signal transduction pathways and gene regulatory mechanisms, induction of selection processes for gene mutations, tumor cell apoptosis and tumor angiogenesis. Most of these mechanisms contribute to tumor progression. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. Therapies that target hypoxic tissues within a tumor would certainly provide improved treatments to patients suffering from tumor-related cancers and/or disorders.
In addition to cancer, there exist a number of hyperproliferative diseases and/or disorders that are associated with the onset of hypoxia in a given tissue. For example, Shweiki et al. explain that inadequate oxygen levels often lead to neovascularization in order to compensate for the needs of the hypoxic tissue. Neovascularization is mediated by expression of certain growth factors, such as vascular endothelial growth factor (VEGF). Shweiki et al., Nature 359:843 (1992). However, when certain tissues or growth factors are either directly or indirectly upregulated in response to hypoxia without sufficient feedback mechanisms for controlling tissue expression, various diseases and/or disorders may ensue (i.e., by hypoxia-aggravated hyperproliferation).
5-Fluorouracil (5-FU), which contains an imide N—H group, is thymidylate synthase inhibitor (antimetabolite) used for the treatment of solid tumors of the head, neck, breast, colon, rectum, liver and pancreas. Thymidylate synthase (TS) catalyzes conversion of deoxyuridine 5′-O-monophosphate (dUMP) to deoxythymidine 5′-O-monophosphate (dTMP). It is believed that 5-FU retards tumor expansion by causing thymidine pools to become depleted in rapidly proliferating tumor cells. See U.S. Pat. No. 5,614,505.
5-FU has a low therapeutic index because of its toxicity at doses lower than therapeutically effective doses, reducing the potential utility. See U.S. Pat. No. 6,702,705. This has led to the development of 5-FU analogs or prodrugs (e.g., 1-(tetrahydro-2-furanyl)-5-fluorouracil, commonly known as ftorafur or tegafur) that slowly release 5-FU upon enzymatic degradation. See, e.g., U.S. Pat. No. 5,719,132. U.S. Pat. No. 3,948,897 describes the synthesis and anti-cancer activity of tegafur, which has the following structure:

5-FU must be anabolized to the level of nucleotides (e.g., fluorouridine- or fluorodeoxyuridine-5′-phosphates) in order to exert its potential cytotoxicity. The nucleosides corresponding to these nucleotides (5-fluorouridine and 5-fluoro-2′-deoxyuridine) are also active antineoplastic agents, and in some model systems are substantially more potent than 5-FU, probably because they are more readily converted to nucleotides than 5-FU is. See U.S. Pat. No. 6,702,705.
U.S. Pat. No. 3,322,747 describes a group of 5-FU analogs or prodrugs having the following structures A and B:
wherein R is acyl, alkyl or aralkyl; R′ is hydrogen, halo, alkyl, amine, alkylamine (e.g., methylamine, dimethylamine, propylamine) or triflouromethyl amine; R″ is alkyl phosphite.
U.S. Pat. No. 5,032,680 describes a group of 2′-deoxy-5-fluorouridine derivatives having the following structure:
wherein R1 is hydrogen or acyl and R2 and R3 are respectively hydrogen, acyl or a group of the formula:
wherein X1 and X2 are respectively oxygen or sulfur, R4 is phenyl, benzyl, or naphthyl each of which may be substituted by alkyl, alkoxyl, alkoxycarbonyl, alkylthio, acyl, halo, trifluoromethyl, nitro, cyano, carboxyl or methylenedioxy and R5 is alkyl, alkenyl or R4, at least one of R2 and R3 being a group of the formula:

U.S. Pat. No. 4,757,139 describes a group of 5-FU analogs or prodrugs having the following structure:
wherein R1 and R2 are the same or different from each other, each representing an alkyl group of 1 to 18 carbon atoms having a carboxyl group as a substituent, or an alkyl group of 9 to 14 carbon atoms, or their pharmacologically acceptable salts.
U.S. Pat. No. 5,808,049 describes a group of 5-FU analogs or prodrugs having the following structure:
wherein R1 is methyl, methoxy or trifluoracetamido; R2 is phenyl, or phenylmethyl; and the absolute configuration of the chiral center is R.
U.S. Pat. No. 5,530,003 describes a 5-FU analog or prodrug having the following structure:

U.S. Pat. No. 6,702,705 ('705 patent) describes antineoplastic nucleotide analogs comprising monosaccharide hexapyranose or hexafuarnose covalently attached to the 3′ or 5′ oxygen of the nucleotide analog. Examples of nucleotide analogs disclosed by the '705 patent include fluorouracil, fluorodeoxyuridine, fluorouridine, arabinosyl cytosine, mercaptopurine riboside, thioguanosine, arabinosyl fluorouracil, azauridine, azacytidine, fluorcytidine, fludarabine. Disclosed monosaccharides (hexapyranose or hexafuranose) include glucose, glycosamine, D-quinovopyranose, galactose, galactosamine, L-fucopyranose, L-rhamnopyranose, D-glucopyranuronic acid, D-galactoypranuronic acid, D-mannopyranuronic acid, D-iodopyranuronic acid, glucose, glycosamine, D-quinovopyranose, galactose, galactosamine, L-fucopyranose, L-rhamnopyranose, D-glucopyranuronic acid, D-galactoypranuronic acid, D-mannopyranuronic acid and D-iodopyranuronic acid.
Mannich bases are known to those skilled in the art. Mannich bases, which undergo facile conversion back to the component parts under physiological conditions, have been investigated as prodrugs. See, e.g., Bundgaard, H. and Moss, J. J. Pharm. Sci. 78(2):122-26 (1989). However, owing to the facile conversion back to the parent drug, the use of Mannich base prodrugs is limited.